Patent EA-004306-B1 (EA)
Title: Non-steroidal (hetero) cyclically substituted acylanilides with mixed gestagen and androgen activity
Inventor: LEHMANN MANFRED
IPC: C07D265/02
Filed: 1998-06-02
Abstract: 1. Compounds of general formula I in which R<1> and R<2> are the same or different and stand for a hydrogen atom, a C1-C5 alkyl group or a halogen atom, and also together with the C-atom of the chain stand for a ring with a total of 3-7 links, R<3> stands for a C1-C5 alkyl group and a partially or completely fluorinated C1-C5 alkyl group, A stands for a mono- or bicyclic carbocyclic or heterocyclic aromatic ring that is optionally substituted by one or more radicals selected from halogen atoms, C1-C5 alkyl groups, C2-C5 alkenyl groups -CR<5>=CR<6>R<7>, whereby R<5>, R<6> and R<7> are the same or different and, independently of one another, mean hydrogen atoms or C1-C5 alkyl groups, hydroxy groups, hydroxy groups that carry a C1-C10 acyl group, a C3-C10 carbalkoxyalkyl group, a C2-C5 cyanoalkyl group, unsubstituted or substituted C3-C10 allyl group, a C3-C10 unsubstituted or substituted propargyl group, a C2-C5 alkoxyalkyl group, a C1-C5 alkyl group that is partially or completely substituted by fluorine atoms, and also selected from the cyano or nitro group, C1-C5 alkoxy groups, C1-C5 alkylthio groups, mono- or disubstituted C1-C10 amino groups, or partially or completely fluorinated C1-C5 alkyl groups, B stands for a carbonyl group or a CH2 group, and Ar stands for a ring system selected from the group of general partial formulas 2-11 in which radicals X<3A>, X<4>, X<5>, X<7> (in partial formula 2), X<4>, X<6>, X<7> (in partial formulas 3 and 4), X<3A>, X<3B>, X<4>, X<6>, X<7> (in partial formulas 5, 6 and 7) or Y<4>, Y<5>, Y<7>, Y<8> (in partial formulas 8, 9, and 11) are the same or different and are selected from hydrogen atoms, C1-C5 alkyl groups, which in addition can contain a hydroxy group that is optionally etherified with a C1-C5 alkyl group or esterified with a C1-C5 alkanoyl group, partially or completely fluorinated C1-C5 alkyl groups, C2-C5 alkenyl groups -CR<5>=CR<6>R<7>, whereby R<5>, R<6>, and R<7> have the above-mentioned meanings, alkynyl groups -C [triple bond] CR<5>, whereby R<5> has the above-mentioned meanings, radicals X<3A> and X<3B> also together with the C-atom of benzocondensed ring system 5, 6 or 7 can form a ring with a total of 3-7 links, and, moreover, radicals X<4>, X<6>, X<7> (in partial formulas 2, 3, 4, 5, 6 and 7) or Y<4>, Y<5>, Y<7>, Y<8> (in partial formulas 8, 9, 10 and 11) are selected from halogen atoms, hydroxy groups, C1-C5 alkoxy groups or C1-C5 alkanoyloxy groups, and if B stands for a CH2 group, the physiologically compatible salts of the compounds of general formula I with acids. 2. Compounds of general formula I according to claim 1 in the form of the racemate or diastereomer mixture. 3. Compounds of general formula I according to claim 1 in the form of separate optical isomers. 4. Compounds of general formula I according to claim 1, characterized in that R<1> and R<2> are the same or different and stand for a hydrogen atom, a methyl or ethyl group, and also together with the C-atom of the chain stand for a cyclopropyl ring. 5. Compounds of general formula I according to claim 1, wherein R<3> stands for a C1-C5 perfluoroalkyl group. 6. Compounds of general formula I according to claim 1, wherein A stands for a benzene, naphthalene or thiophene ring that is optionally substituted by one or more radicals selected from fluorine atoms, chlorine atoms, bromine atoms, methyl groups, ethyl groups, vinyl groups, hydroxy groups, methoxy groups and ethoxy groups. 7. Compounds of general formula I according to claim 1, wherein X<3A> stands for a hydrogen atom or a C1-C5 alkyl group. 8. Compounds of general formula I according to claim 1, wherein X<3A> and X<3B> are the same or different and stand for a hydrogen atom or a C1-C5 alkyl group. 9. Compounds of general formula I according to claim 1, wherein X<4>, X<6> and X<7> are the same or different and stand for, independently of one another, a hydrogen atom or a halogen atom. 10. Compounds of general formula I according to claim 1, wherein Y<4> stands for a C1-C5 alkyl group or a C1-C5 perfluoroalkyl group. 11. Compounds of general formula I according to claim 1, wherein Y<5>, Y<7> and Y<8> are the same or different and stand for, independently of one another, a hydrogen atom or a halogen atom. 12. Compounds of general formula I according to claim 1, wherein R<1> and R<2> are the same or different and stand for a hydrogen atom, a methyl or ethyl group, and also together with the C-atom of the chain stand for a cyclopropyl ring, and R<3> stands for a C1-C5 perfluoroalkyl group, A stands for a benzene, naphthalene or thiophene ring that is optionally substituted by one or more radicals selected from fluorine atoms, chlorine atoms, bromine atoms, methyl groups, ethyl groups, vinyl groups, hydroxy groups, methoxy groups, and ethoxy groups, and either X<3A> stands for a hydrogen atom or a C1-C5 alkyl group, or X<3A> and X<3B> are the same or different and stand for a hydrogen atom or a C1-C5 alkyl group and X<4>, X<6> and X<7> are the same or different, and stand for, independently of one another, a hydrogen atom or a halogen atom, or Y<4> stands for a C1-C5 alkyl group or a C1-C5 perfluoroalkyl group, and Y<5>, Y<7> and Y<8> are the same or different and stand for, independently of one another, a hydrogen atom or a halogen atom, and the other substituents all have the meanings that are indicated in Formula I. 13. Compounds of general formula I according to claim 1, in which Ar stands for a ring system of partial formula 6. 14. Compounds of general formula I according to claim 1, in which Ar stands for a ring system of partial formula 7. 15. Compounds of general formula I according to claim 1, in which Ar stands for a ring system of partial formula 10. 16. Compounds of general formula I according to claim 1, in which Ar stands for a ring system of partial formula 11. 17. Compounds of general formula I according to claim 1, namely 4-Bromo-5-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethylvaleroylamino)phthalide, 6-bromo-5-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethylvaleroylamino)phthalide, 5-(2-hydroxy-4-methyl-2-pentafluoroethyl-4-phenylvaleroylamino)phthalide, 5-[2-hydroxy-4-(3-methoxyphenyl)-4-methyl-2-trifluoromethylvaleroylamino]phthalide, 5-[2-(hydroxy-4-(4-methoxyphenyl)-4-methyl-2-trifluoromethylvaleroylamino]phthalide, 5-[2-hydroxy-4-(2-hydroxyphenyl)-4-methyl-2-trifluoromethylvaleroylamino]phthalide, 5-[4-(2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]phthalide, 5-[4-(4-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-phthalide, 5-[4-(4-chlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]phthalide, 5-[4-(4-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-phthalide, 5-[2-hydroxy-4-methyl-4-(4-tolyl)-2-trifluoromethylvaleroylamino]phthalide, 5-[2-hydroxy-4-methyl-4-(3-tolyl)-2-trifluoromethylvaleroylamino]phthalide, 5-[4-(4-cyanophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]phthalide, 5-[4-(3,4-dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]phthalide, 5-[4-(3,5-dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]phthalide, 5-[2-hydroxy-4-(2-methoxy-5-methylphenyl)-4-methyl-2-trifluoromethylvaleroylamino]phthalide, 5-[4-(5-chloro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]phthalide, 5-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]phthalide, 5-[2-hydroxy-4-(2-hydroxy-5-methylphenyl)-4-methyl-2-trifluoromethylvaleroylamino]phthalide, 5-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]phthalide, 5-[4-(2-fluoro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]phthalide, 5-[4-(3-fluoro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]phthalide, 5-(2-hydroxy-4-phenyl-2-trifluoromethylvaleroylamino)phthalide, 5-[2-hydroxy-4-(2-methoxyphenyl)-4-methyl-2-trifluoromethylvaleroylamino]phthalide, 5-[4-(5-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]phthalide, 5-(2-hydroxy-4-phenyl-2-trifluoromethylpentylamino)phthalide, 5-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethylpentylamino)phthalide, 5-[4-(4-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentylamino]phthalide, 5-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentylamino]phthalide, 6-acetyl-5-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethylvaleroylamino)phthalide, 5-[4-(3-fluoro-4-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]phthalide, 5-[4-(3-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]phthalide, 6-(3-hydroxy-3-methyl-1-butinyl)-5-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethylvaleroylamino)phthalide, 6-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethylvaleroylamino)-4-methyl-2,3-benzoxazin-1-one, 6-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethylvaleroylamino)-4-trifluoromethyl-2,3-benzoxazin-1-one, 4-ethyl-6-(2-hydroxy-4-phenyl-2-trifluoromethylpentylamino)-2,3-benzoxazin-1-one, 4-ethyl-6-[2-hydroxy-4-(2-methoxyphenyl)-4-methyl-2-trifluoromethylvaleroylamino]-2,3-benzoxazin-1-one, 6-[2-hydroxy-4-(2-methoxyphenyl)-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one, 4-ethyl-6-[2-hydroxy-4-methyl-4-(4-methylphenyl)-2-trifluoromethylvaleroylamino]-2,3-benzoxazin-1-one, 6-(4-(4-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-ethyl-2,3-benzoxazin-1-one, 4-ethyl-6-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-2,3-benzoxazin-1-one, 6-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one, 1-(4-nitro-3-trifluoromethylanilino)-4-phenyl-2-trifluoromethyl-2-pentanol, 5-(2-hydroxy-4,4-dimethyl-2-trifluoromethyl-5-hexenoylamino)phthalide, 5-[2-hydroxy-3-(1-phenylcyclopropyl)-2-trifluoromethylpropionylamino]phthalide, 5-[2-hydroxy-3-(1-phenylcyclobutyl)-2-trifluoromethylpropionylamino]phthalide, 5-[2-hydroxy-3-(1-phenylcyclohexyl)-2-trifluoromethylpropio